Chronic congestive heart failure is characterized by neurohumoral excitation (NHE) that contributes to the progression of end-stage disease and the premature demise of the patient. In the past few decades, most of the therapeutic measures were targeted against the activation of the neurohormonal system, and these strategies have clearly reduced mortality and morbidity. However, the clinical course of heart failure (HF) is progressive and the long-term prognosis remains dismal, suggesting that other mediators might be involved in NHE. Currently, immune mediated mechanisms have been recognized to play an important role in the pathogenesis of HF. Recently, we reported for the first time that cytokines are activated in the brain early after myocardial infarction. We also showed that blockade of cytokines attenuated NHE and angiotensin II receptor protein in the hypothalamus and the heart of HF rats. Therefore, we hypothesize that cytokines, acting either directly or via an interaction with the renin-angiotensin system (RAS), contribute to NHE in heart failure. The specific aims of this application are: 1. Peripheral cytokines drive NHE in heart failure, either directly or via an interaction with the peripheral RAS. 2. Central nervous system cytokines activate NHE in heart failure, either directly or via an interaction with products of intrinsic brain RAS. 3. Cardiac sympathetic afferents contribute to brain cytokine activation and bring about NHE in heart failure. This proposal will focus on understanding the contribution of peripheral and central nervous system influences of three cytokines (interleukin-1beta, tumor necrosis factor-alpha and interleukin-6) and angiotensin on NHE in HF. This will be accomplished by integrating a combination of molecular, cellular, electrophysiological and in vivo (rat and mouse model of HF) experimental approaches. The central link between cytokines and the neurohumoral system in HF may lead to a better understanding of the progression of the disease process and ultimately lead to new and effective strategies to treat HF.